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PubMed1982

A correlation between cancer metastases and the fluidity of cancer cell membrane.

Male Donryu rats weighing from 100 to 120 g were transplanted with AH100B, AH66F or Yoshida sarcoma (YS) cells intraperitoneally. After collecting ascites, while not bloody, the cancer cells were washed three times with Dulbecco's phosphate buffered saline (PBS) without Ca++ and Mg++ (pH 7.2). Then, each sediment was suspended in PBS mentioned above. Each suspension in which 10 million of cancer cells were contained was violently vibrated with a definite amount of 5-doxyl stearic acid and spin labeling of cancer cell membrane was done. Furthermore, each specimen thus obtained was subjected to measurements of ESR spectra and the order parameter was determined from the spectra. The order parameter of AH100B was the highest and that of YS the lowest at each temperature measured from 5 degrees C to 35 degrees C. YS cells have been reported to be found in blood stream within 24 hr, AH66F cells in a day and AH100B cells in 10 days or more after intraperitoneal inoculation. The results obtained here suggest that the accelerated fluidity of cancer cell membrane is related with the cancer metastasis.

Animals↗

PubMed1976

[Study on tumor affinity of technetium-99m-labeled radiopharmaceuticals. (1) 99mTc-pertechnetate, 99mTc-human serum albumin, and 99mTc-trasylol].

This paper describes biologic distributions, sequential images and macroautoradiograms of 99mTcO4 (pertechnetate), 99mTc-Sn-HSA (human serum albumin) and 99mTc-Sn-TSL (trasylol) in tumor-bearing mice as the first report on tumor affinity of 99mTc-labeled radiopharmaceutical. (1) Maximum tumor concentration (% administered dose/g of tissue weight) of 99mTcO4, 99mTc-HSA and 99mTc-TSL in Ehrlich's tumor-bearing mice resulted in 2.03+/-0.57 at 1 hr, 4.02+/-0.19 at 3 hr and 1.97+/-0.31 at 1 hr respectively. (2) However, tumor to blood concentration ratio of 99mTc-HSA was lowest among them. (3) The corrected tumor accumulation (% 100g dose/g of tissue wt.=% dose/% body weight) of 99mTc-TSL to Ehrlich's tumor in mouse was not different from that of Yoshida's sarcoma in rat, on the contrary to our expectation that the tumor concentration of 99mTc-TSL in them might be different due to differency of the tissue fibrinolytic activity between the respective tumors. (4) Sequential images of the implanted tumor in mouse was best positively delineated with 99mTc-HSA. (5) Macroautoradiograms of Ehrlich's tumor with 99mTcO4, 99mTc-HSA and 99mTc-TSL demonstrated the following findings: all of them were not only accumulated markedly into the tumor cells which were shown as basophilic tissue with Hämatoxylin-Eosin staining but also accumulated around the tumor tissue and on the interstitial tissue which were stained as eosinophilic tissue with the above same staining.

Animals↗

PubMed1981

Rubeomycin, a new anthracycline antibiotic complex. I. Taxonomy of producing organism, isolation, characterization and biological activities of rubeomycin A, A1, B and B1.

A new antibiotic complex has been obtained from the cultures of an actinomycete, strain FA-1180, isolated from a soil sample collected at lake side of Biwa in Japan. On the basis of taxonomic studies the producing microorganism is designated as Actinomadura roseoviolacea var. biwakoensis nov. var. The antibiotic complex belongs to the class of anthracycline glycoside antibiotics. All components form deep red fine needles on crystallization; components are named rubeomycin A, A1, B and B1. These components exhibit activity against Gram-positive bacteria as well as Yoshida sarcoma cell in vitro. These components are also effective on P388 leukemia.

Animals↗

PubMedDate not supplied

Antiproliferative and cytotoxic effects of N,N-diethylaminoethyl ethers of flavanone oximes: a comparison with anthracycline(s), anthraquinone and nitroxides action.

Since flavanone oximes derivatives (ethers) have been shown to modulate the growth of Yoshida Sarcoma cells in vivo and to induce apoptosis, the effects of these substances on immortalized cell lines growth were examined. Cell viability and sensitivity to investigated substances was measured by the modified tetrazolium salt (MTT) assay. The antiproliferative effects were expressed as IC50 and IC90, respectively. There were very substantial differences in the dose-dependency of the observed antiproliferative and cytotoxic effects. The structure-activity relationship was evident and revealed that the substitution at B-ring of molecule seems to be an important factor in flavanone oxime (ether) potency. Compared to anticancer drugs (doxorubicin, aclarubicin and mitoxantrone) flavanone oximes displayed cytotoxicity at considerably higher concentrations. The antiproliferative action of the investigated model nitroxides depended on the free radical part of the molecule. N-hydroxy derivative (reduced cation form) did not influence cells proliferation and nor display any cytotoxicity at the applied range about 60 times higher than those of flavanone derivatives. Taken together it seems reasonable to suggest that flavanone oxime(s) (ethers) as compared with antracycline(s), anthraquinone and nitroxides might be especially good candidates for in the future development of new therapeutic techniques.

3T3 Cells↗

PubMedDate not supplied

Morphology of the designed biodegradable cisplatin microsphere.

We observed the morphological changes in microspheres containing cisplatin (CDDP) embedded in poly-d,l,-lactic acid (PLA) and polyethylene glycol acid (CDDP-PPMS). The in vitro release of CDDP from CDDP-PPMS continued for more than four weeks. Scanning electron microscopy revealed that though the particles of CDDP-PPMS were spherical and superficially smooth, small pores with a superficial irregularity appeared six months later. CDDP-PPMS particles were found in the stomata of the omentum after intraperitoneal administration. When CDDP-PPMS was administered after Yoshida sarcoma cells were intraperitoneally transplanted, CDDP-PPMS was observed histologically in the necrotic tissues of the omentum. These experimental results confirmed the release of CDDP from CDDP-PPMS and the histological efficacy of CDDP-PPMS in the omentum against peritoneal metastasis.

Animals↗

PubMed2001

D-24851, a novel synthetic microtubule inhibitor, exerts curative antitumoral activity in vivo, shows efficacy toward multidrug-resistant tumor cells, and lacks neurotoxicity.

N-(pyridin-4-yl)-[1-(4-chlorbenzyl)-indol-3-yl]-glyoxyl-amid (D-24851) is a novel synthetic compound that was identified in a cell-based screening assay to discover cytotoxic drugs. D-24851 destabilizes microtubules and blocks cell cycle transition specifically at G2-M phase. The binding site of D-24851 does not overlap with the tubulin binding sites of known microtubule-destabilizing agents like vincristine or colchicine. In vitro, D-24851 has potent cytotoxic activity toward a panel of established human tumor cell lines including SKOV3 ovarian cancer, U87 glioblastoma, and ASPC-1 pancreatic cancer cells. In vivo, oral D-24851 treatment induced complete tumor regressions (cures) in rats bearing Yoshida AH13 sarcomas. Of importance is that the administration of curative doses of D-24851 to the animals revealed no systemic toxicity in terms of body weight loss and neurotoxicity in contrast to the administration of paclitaxel or vincristine. Interestingly, multidrug-resistant cell lines generated by vincristine-driven selection or transfection with the Mr 170,000 P-glycoprotein encoding cDNA were rendered resistant toward paclitaxel, vincristine, or doxorubicin but not towards D-24851 when compared with the parental cells. Because of its synthetic nature, its oral applicability, its potent in vitro and in vivo antitumoral activity, its efficacy against multidrug-resistant tumors, and the lack of neurotoxicity, D-24851 may have significant potential for the treatment of various malignancies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1992

Glutamine antagonist with diet deficient in glutamine and aspartate reduce tumor growth.

This study was designed to investigate whether a combination of a glutamine antagonist (DON) and a diet deficient in glutamate and aspartate (AG) altered glutamine metabolism in tumor tissue, and inhibited tumor growth. In experiment-1, 21 male Donryu rats were fed with AG and implanted with Yoshida's Sarcoma. Of them, 7 rats were sacrificed on the 5th day (group AG), other 7 were sacrificed next day (group AG-1) and the remaining 7 were injected with DON on the 5th day and sacrificed next day (group AG+D). The tumor weight of group AG+D was significantly lower than of group AG, or of group AG-1. In experiment-2, of 23 rats, 9 were fed with control diet and 14 were fed with AG and implanted. 12 were sacrificed on the 5th day (group C, AG), and 11 were injected with DON on the 5th day and sacrificed next day (group C+D, AG+D). The reduced ratio of tumor weight in group C+D and group AG+D were 25% and 67%, respectively. These results show that the tumor growth could be inhibited by using metabolic antagonist of glutamine, and that it had synergistic effect in conjunction with the imbalanced diet.

Amino Acids↗

PubMedDate not supplied

Preliminary study of the optimal dosing schedule for oral UFT/leucovorin chemotherapy.

BACKGROUND: We evaluated the optimal dosage schedule for combined oral chemotherapy using uracil/tegafur (UFT) and leucovorin (LV) in Yoshida sarcoma-bearing rats. MATERIALS AND METHODS: The antitumor activity and survival effect were compared between two schedules, thrice daily administration on 5 days of the week followed by 2 drug-free days (schedule A) and twice daily on 7 days of the week (schedule B). RESULTS: Significant tumor growth inhibition and improved survival rate were seen with both schedules of the UFT/LV group as compared to their respective control groups. Tumor growth inhibition was significantly greater in schedule A than schedule B. The number of survivors on day 60 after the tumor inoculation was higher in schedule A although the survival rate did not differ significantly. CONCLUSION: Administration of UFT/LV for 5 days of the week seemed to exhibit superior antitumor activity, with no increase in the incidence of adverse effects, as compared with the consecutive daily dosing schedule.

Animals↗

PubMed1992

Synthesis and cytotoxicity of shikimate analogues. Structure:activity studies based on 1-crotonyloxymethyl-3R,4R,5R-trihydroxycyclohex-2-enone.

Syntheses are described for and structure:activity studies undertaken of the anti-tumour activity of (2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-+ ++enone) (1) and its analogues 1-crotonyloxymethyl-(3R,4S,5R)-3,4,5-trihydroxycyclohex-1-en e (3), 1-crotonyloxymethyl-(3R,4S,5S)-3,4,5-trihydroxycyclohexene (4) and 2-crotonyloxymethyl-2-cyclohexenone (5), which differ from 1 in the presence/absence of the cyclic keto group and/or the stereochemistry at one of the -OH bearing carbon atoms. None of the above compounds, including 1, directly inhibited glyoxalase I, isolated for the first time to homogeneity from rat Yoshida sarcomas and for which a purification protocol was developed. The apparent inhibition of glyoxalase I by 1 and 5 (but not detected for 4 or 3) could be explained by reaction of 1 and 5 with the glutathione present in the assay buffer and the consequent depletion of substrate. 1 and 5 were found to react readily with glutathione whereas 4 and 3 did not react. In vitro chemosensitivity studies against a panel of tumour cell lines of both mouse and human origin showed that in parallel with their thiol reactivity, 1 and 5 exhibited significant in vitro cytotoxicity whereas 4 and 3 did not. Concentrations of drug required to cause 50% cell kill (ID50 values) were in the range 0.5-19 microM (0.1-2.8 micrograms/ml) for 5, and 3-44 microM (0.7-10 micrograms/ml) for 1. The structural features causing the differences in antitumour effects were localized on this basis to the alpha,beta-unsaturated ketone linkage as opposed to the stereochemistry of the (trihydroxy) alcoholic sites.

Animals↗

PubMed1975

Changes of enzyme activities in spleen lymphocytes from tumor-bearing rats.

The induction of concomitant immunity was studied in Donryu strain rats with Yoshida ascites sarcoma cells. The changes of enzyme activity in spleen lymphocytes were also examined in normal and tumor-bearing rats. The concomitant immunity was detected 1 week after transplantation of tumor cells. Extended metastases were found 2 weeks after transplantation. The enzyme activities of ATPase and acid phosphatase were definitely higher than that of normal rat 1 week after the transplantation but decreased to lower level than normal 2 weeks later. On the other hand, alkaline phosphatase activity increased 3 times at 1 week after the transplantation and remained at the same level even at 2 weeks later.

Acid Phosphatase↗

PubMed1990

Mechanism of host cell membrane modification by tumour: a model for paraneoplastic syndromes.

A not well-appreciated but clinically important aspect of malignant tumours is their effects on distantly located host cells. The effects, termed paraneoplastic syndromes, also pose an intriguing mechanistic problem: how do malignant cells influence properties of host cells not in contact with them? Erythrocytes from the circulation of rats bearing intraperitoneal Yoshida ascites sarcoma exhibit higher agglutinability with concanavalin A (Con A) than the cells from normal animals. Since the tumour and the red cells are not in contact, the enhanced agglutinability of the latter is a paraneoplastic effect. The mechanism by which the tumour brings about this effect is investigated as a model for paraneoplastic syndromes. The cell-free ascites fluid is able to impart high agglutinability on cells from normal animals in vitro. Also, when injected intraperitoneally in normal animals, the ascites fluid is able to enhance the agglutinability of erythrocytes in circulation. Apparently the tumour produces a substance(s) that appears in the ascites fluid and is able to diffuse into circulation, explaining the mechanism by which it can reach distant sites. From the cell-free ascites fluid three fractions have been isolated that are active in vitro. Of these, only one showed activity in vivo. From this fraction, a glycoprotein has been purified to homogeneity that confers maximal Con A-agglutinability on normal erythrocytes at 8 x 10(-7)M, at which concentration 6,400 molecules bind per cell. The protein has a molecular weight of 600 kDa in the native state and a pI of 5.35. It is made up of 4 identical subunits of Mr 170,000. It is detected in the plasma of tumour-bearing but not normal rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

The subrenal capsule assay in immunocompetent mice--the inevitable role of histopathology in assessment of this method as a tool determining tumor sensitivity to cytostatic drugs.

The subrenal capsule assay (SRC) in immunocompetent mice became one of commonly used approaches to evaluating the efficiency of cytostatic therapy. A comparison of the classical macroscopic evaluation according to the Bogden diagram with results of the histopathologic examination in 118 mice with implanted Yoshida sarcoma or human rectal adenocarcinoma demonstrated the tumor to be present to different extent only in 26 out of 50 macroscopically positive cases and, on the other hand, it was found in 3 out of 68 macroscopically negative animals. Histological changes in these cases, as well as a study of the dynamics of the development of histopathologic changes after tumor implantation and the changes after implantation of inert materials demonstrated that the resorptive and reparative granuloma, originating in immunocompetent mice under the renal capsule after implanting the tumor or other materials, simulates perfectly the growth of the tumor infiltrate. For this reason we consider this method in immunocompetent mice as unreliable when there is no parallel histological examination.

Animals↗

PubMed1988

[Targeting chemotherapy with activated carbon particles adsorbing anti-cancer drugs].

A new drug delivery system comprising activated carbon particles adsorbing anticancer drugs was developed. Activated carbon particles have affinity to the regional lymph-nodes and the tumor surface. When activated carbon particles adsorbing anticancer drug were administered into the tissues or serosal cavity, they remained for a long time at the site of application, and released the drug slowly. Activated carbon particles adsorbing mitomycin C (MMC-CH) were prepared for the use of an intracavitary administration. In animal experiment tissues, MMC-CH distributed a large amount of mitomycin C to the intraperitoneal tissues, while there was a low level of mitomycin C in the whole body. The LD50 value of MMC-CH was 5.3 times as high as that of mitomycin C aqueous solution. The therapeutic index (LD50/ED50) of the MMC-CH therapy was 3.1 times higher than that of the mitomycin C aqueous solution in Yoshida sarcoma ascites. Clinical trials of MMC-CH were performed in 81 patients with malignant effusion. Fifty-one of the 81 patients responded well. Activated carbon particles adsorbing peplomycin (PEP-CH) were prepared for chemotherapy against lymphatic metastasis. A high level of peplomycin was distributed to regional lymph nodes for a long time, when it was injected into the gastric wall of dogs. In animal experiments using MH 134 tumor, the therapeutic efficacy of PEP-CH on the lymphatic metastasis was greater than that of peplomycin aqueous solution. Clinical trials were carried out in 7 patients with esophageal cancer who did not undergo surgery. The local response rate was 85% and the survival time was 9.4 months in average including 5 survivors.

Animals↗

PubMed1987

Nucleotide and deduced amino acid sequences of two distinct cDNAs for rat phosphoribosylpyrophosphate synthetase.

The rat Yoshida sarcoma (YS) cDNA library was screened using oligonucleotide probes designed from peptide sequences of rat phosphoribosylpyrophosphate synthetase, and two distinct clones were obtained. Nucleotide sequencing revealed that both clones encode 317 amino acids containing the peptide sequences. The deduced amino acid sequences of the two differ only by 13 residues (96%) identity), whereas the nucleotide sequences are relatively divergent (81% identity in the coding regions). These results, together with N-terminal amino acid sequencing data, suggest the existence of two different subunits of this enzyme, designated as PRS I and II (their genes as PRPS1 and PRPS2). Transcripts of 2.3 and 3.7 kilobases were detected in YS cells and rat liver by Northern blot analysis, using PRS I and II cDNAs respectively, as probes. In the liver, the expression of both genes increased after partial hepatectomy.

Amino Acid Sequence↗

PubMed1986

Effects of fatty acid modification of ascites tumor cells on pulmonary metastasis in rat.

Yoshida sarcoma cells were incubated with each of 4 different saturated and 17 different unsaturated fatty acid methyl and ethyl esters in order to modify the fatty acid composition of the cell membrane, and a possible correlation between the lipid fluidity of the cell membrane and the metastatic efficiency was studied. Almost all the unsaturated fatty acids used were incorporated into the tumor cell membrane, resulting in an increase of fluidity. In contrast, the incorporation of saturated fatty acids brought no change in fluidity. Exogenous treatment of the cells with palmitoleic acid (16:1, cis) induced a remarkable increase of membrane lipid fluidity resulting in easier passage of modified cells through capillary vessels, which was detected in an in vitro perfusion test of the lung. Intravenous injection of the modified cells resulted in fewer metastatic foci in the lung as compared with that of unmodified cells. A similar effect on lung metastasis was also observed in exogenous modification of the cells by linoleic acid (18:2, cis) or linolenic acid (18:3, n-3). On the other hand, although exogenous eicosapentaenoic acid (20:5, n-3) and docosahexaenoic acid (22:6, n-3) treatments induced a slight increase in the lipid fluidity of the cells, intravenous injection of the cells produced a significant increase in their metastatic potential in the lung. Interestingly, the treatment with 20:5 and 22:6 produced increased stickiness of the cells to a glass surface and reduced cellular passage through the vessels as detected by the lung perfusion test. Thus, the present results suggested that selective modification of membrane fatty acid may be a useful method for artificial regulation of the ability of circulating tumor cells to pass through vessels.

Animals↗

PubMed1986

[Comparison of continuous venous infusion of 5-FU and FT-207 under total parenteral nutrition].

Yoshida sarcoma-bearing rats were continuously infused with 5-FU at a dose of 20 mg/kg/day, and FT-207 at a dose of 40 mg/kg/day, 100 mg/kg/day or 140 mg/kg/day under TPN. After 4 days, rats were sacrificed and the 5-FU and FT-207 concentrations in their organs were measured. The 5-FU level in the tumor was almost the same at when 5-FU was injected at 20 mg/kg/day and FT-207 at 140 mg/kg/day. This 5-FU level in the tumor was twice and four times higher than that of the group injected with FT-207 at 100 mg/kg/day and 40 mg/kg/day. The 5-FU level in the tumor in all four groups was almost twice as high as that in the stomach, intestine and kidney, 7-10 times higher than that in the liver, and 10-30 times higher than that in serum. The FT-207 levels in the alimentary tract, kidney, tumor and serum were almost the same. The conclusion of our preliminary research is that FT-207 is recommended for use in continuous infusion at 7 times the dose of 5-FU when injected under TPN.

Animals↗

PubMedDate not supplied

Enhanced chemotherapeutic efficacy on carcinomatous peritonitis using a new dosage form in animal experiments.

A new dosage form, comprising Mitomycin C adsorbed on activated carbon particles (MMC-CH) was studied for its local therapeutic effects on carcinomatous peritonitis. After intraperitoneal transplantation of 10(7) cells of Yoshida sarcoma, drug treatment was given on day 2. The ED50 value on ascites was determined with Litchfield-Wilcoxon's method on day 6. The therapeutic index (LD50/ED50) on ascites in MMC-CH treatment was 3.09 times higher than that in Mitomycin C solution treatment.

Adsorption↗

PubMed1988

Therapy of P388 leukemia with benzaldehyde.

Optimal schedules of benzaldehyde (50-100 mg kg-1 intraperitoneally) on day 1 or on several days after inoculation of 10(5) P388 leukemia cells to DBA 2J mice increased survival by 70-100%. No significant prolongation of survival was observed between the various schedules of benzaldehyde treatment. Significantly longer survival was observed on day 30 after benzaldehyde treatment with 100 mg kg-1 on day 1 or 50 mg kg-1 on days 1-4 as compared to untreated controls, but no cure was achieved with any schedule and dose of benzaldehyde. No or minimal activity of benzaldehyde on L1210 and L5178Y leukemias, Ehrlich adenocarcinoma and Yoshida sarcoma was observed.

Animals↗